The dystrophinopathies are pathologies caused by anomalies in the DMD gene that encodes a subsarcolemmal protein called dystrophin. With regard to the large deletions, the most frequent genetic alteration, the severity of the phenotype is primarily conditioned by the impact of the mutation on the protein reading frame of the dystrophin transcript. Dystrophin is absent in Duchenne muscular dystrophy (DMD) due to mutations disrupting the open reading frame. In a milder form of the disease, Becker muscular dystrophy, mutations create shortened but in-frame transcripts that encode a partially functional dystrophin. The dystrophin structure (central rod-domain made of 24 spectrin-like repeats) tolerates large internal deletions (1) which led to the development of two main therapeutic strategies: classical gene therapy with transfer of functional micro-dystrophin cDNAs in muscles, and targeted exon skipping. Both approaches have shown encouraging results using adeno-associated viral (AAV) vectors, which allow efficient gene transfer into muscles. Exon skipping strategy converts an out-of-frame mutation into an in-frame mutation leading to an internally deleted but partially functional dystrophin. This therapeutic approach has demonstrated some success using antisense oligonucleotides (AONs), in particular in recent clinical studies (2-5). AONs have the enormous advantage of not being immunogenic but have the disadvantage of having to be regularly injected to maintain therapeutic benefit. We and others have shown that alternatively the antisense sequences could be introduced into skeletal or cardiac muscles using a small nuclear RNA such as U7snRNA or U1 snRNA (6-8). These therapeutic molecules are vectorised in AAV particles which ensure a permanent production of the therapeutic antisense in dystrophin-deficient murine models (7-9), as well as in the dystrophin-deficient dog GRMD (10; 11). A one-shot treatment of AAV-U7 is sufficient to attain substantial levels of restored quasi-dystrophin, which is associated with a significant improvement of the muscle force. AAV genome fate in dystrophic muscles is of importance considering the viral capsid immunogenicity that prohibits today recurring treatments (12). Since muscular dystrophies are characterized by repeated cycles of necrosis-regeneration and because AAV vectors display a non integrative episomal genome, we hypothesized that AAV-U7 could be lost during the necrosis of dystrophic myofibers. Indeed, we followed therapeutic viral genomes during AAV-U7-mediated exon skipping therapy in the severe dystrophic dKO mice and the GRMD dogs after optimal dystrophin rescue and showed that dystrophin restoration decreased significantly after one year in various skeletal muscles which was correlated with important viral genome loss (13; 11). Importantly, we showed that the moderately dystrophic mdx muscles lose non therapeutic viral genomes quickly after the injection and that this loss is strongly slowed down when high doses of viral genomes restore dystrophin quickly at the sarcolemma (13). Importantly, no similar rapid loss of AAV genomes is observed from normal control muscle. Therefore, we previously proposed, to achieve long-term restoration of dystrophin expression, a two-step treatment with firstly, a single systemic injection of AAV-U7 vector to induce a strong and widespread expression of dystrophin in muscles, and secondly, recurrent systemic injections of antisense oligonucleotides to prevent the progressive reappearance of a dystrophic phenotype caused by the partial loss of AAV genomes over time (13). However, improved methods for long-term restoration of dystrophin expression are still needed.